Episode #58 Sugammadex Administration: Anaphylaxis and Recurarization Revisited

August 17, 2021

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Welcome to the next installment of the Anesthesia Patient Safety podcast hosted by Alli Bechtel.  This podcast will be an exciting journey towards improved anesthesia patient safety.

Today on the show we talk about one of the featured articles from the June 2020 APSF Newsletter, “Postoperative Recurarization After Sugammadex Administration Due to the Lack of Appropriate Neuromuscular Monitoring: The Japanese Experience” by Tomoki Sasakawa, MD, PhD; Katsuyuki Miyasaka, MD, PhD; Tomohiro Sawa, MD, PhD; Hiroki Iida, MD, PhD. You can find the article here. https://www.apsf.org/article/postoperative-recurarization-after-sugammadex-administration-due-to-the-lack-of-appropriate-neuromuscular-monitoring-the-japanese-experience/

Table 1. Recommended Doses of Sugammadex for Reversal of Neuromuscular Blockade Based on Neuromuscular Monitoring12

Level of Neuromuscular Blockade Sugammadex Dose12 (mg/kg)
(Reappearance of T2 in response to TOF stimulation)
(At reappearance of 1 or 2 PTCs)
Immediate reversal of neuromuscular blockade
(3 minutes after an intubating dose of rocuronium bromide)

T2, second twitch. TOF, train-of-four. PTC, post-tetanic count.

Goals to increase safety with perioperative neuromuscular blockade:

  • There is a need for medical device manufacturers to create neuromuscular monitors that are easy to use, safe, reliable, and affordable
  • There is a need for anesthesia professionals to use neuromuscular monitoring to guide reversal with Sugammadex so that the patients receive the appropriate dose at the right time.
  • Stay vigilant for clinical signs of recurarization, anaphylaxis, and other postoperative complications.

Next up, we review the development of anaphylaxis following Sugammadex administration. We are reviewing the article, “Current Status of Sugammadex Usage and the Occurrence of Sugammadex-Induced Anaphylaxis in Japan” by Tomoronori Takazawa, MD, PhD; Katsuyuki Miyasaka, MD, PhD; Tomorhiro Sawa, MD, PhD; Hiroki Iida, MD, PhD. Check out the article here: https://www.apsf.org/article/current-status-of-sugammadex-usage-and-the-occurrence-of-sugammadex-induced-anaphylaxis-in-japan/

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© 2021, The Anesthesia Patient Safety Foundation

Hello and welcome back to the Anesthesia Patient Safety Podcast.  My name is Alli Bechtel and I am your host. Thank you for joining us for another show. In November of 2020, we discussed postoperative recurarization and Sugammadex on episode #20. This is one of the most popular episodes of all time and it is a review of one of the most popular articles on our website. Today, we are going to revisit episode #20 before diving into another important topic related to Sugammadex administration, anaphylaxis.

But before we dive into today’s episode, you’ve heard me recognize our corporate supporters on this show, but there’s another supporter who is absolutely essential – YOU! Every individual donation matters so much. Please visit APSF.org and click on the Our Donors heading and consider making a tax-deductible donation to the APSF.

And now, let’s take a listen as we revisit episode #20. Here we go…

[Episode 20 Clip] We are going to talk about one of the featured articles from the June 2020 APSF Newsletter, “Postoperative Recurarization After Sugammadex Administration Due to Lack of Appropriate Neuromuscular Monitoring: The Japanese Experience” written by Sasakawa, Miyasaka, Sawa, and Iida. You can follow along with us from the APSF website by clicking on the Newsletter heading, 4th one down is newsletter archives. Then click on the June 2020 Newsletter. The article is the third featured article.

Are you using Sugammadex at your institution? Sugammadex is a medication that very quickly reverses neuromuscular blockade from rocuronium and other nondepolarizing aminosteroid muscle relaxant medication by selective encapsulation. This article focuses on the experience of anesthesia professionals in Japan using this medication which was first used in Japan in 2010 and has been given to about 12.32 million patients in the following 8 years. Sugammedex has helped to decrease the risk of postoperative residual neuromuscular blockade from about 25-60% with reversal with neostigmine to only 1-4% with Sugammadex reversal. It is a safe and effective medication, but that is not where this story ends.  At the end of 2018, there were 36 cases of recurrence of neuromuscular blockade reported in Japan.  This led to the Safety Committee of the Japanese Society of Anesthesiologists publishing a warning about using correct dosing for Sugammadex in 2019. The correct dosing depends on the patient’s body weight and depth of neuromuscular blockade. I will include the table for this in the show notes as well.  The correct dose for a patient with a moderate neuromuscular block as evidenced by the reappearance of T2 following train of four simulation is 2 mg per kg. Patient’s with a deep block with 1-2 on post-tetanic count, can be reversed with 4mg per kg. Finally, for immediate reversal, such as after 3 minutes of administration of rocuronium for intubation, administration of 16mg per kg is appropriate.  After reversal, it is important to monitor for any signs of an anaphylactic reaction or recurarization and monitor for return to fully intact neuromuscular function.

Let’s look closer at these cases. Many of the patients received inappropriate doses of Sugammadex without neuromuscular monitoring and inadequate management after Sugammadex administration. We have talked about this before but perioperative neuromuscular monitoring with a quantitative device is so important to help prevent postoperative residual neuromuscular blockade. Quantitative monitoring is an objective monitor for the degree of muscle relaxation and can be done with accelerometer or electromyograms in addition to electric nerve stimulation. The advantage of this monitoring is that it provides an objective measure of the train of four to determine with the recovery reaches the point of a train of four ratio greater than 0.9. Quantitative monitors can also provide information about post-tetanic count for patients who have a deeper neuromuscular blockade. Qualitative monitors are still used frequently and depend on the anesthesia professionals subjective assessment of palpating or observing muscle contractions after nerve stimulation from the device. With qualitative devices, it is possible to get an estimate for the train of four count, but anesthesia professionals are unable to determine accurately and reliably when the train of four ratio is greater than 0.9 which is imperative for perioperative neuromuscular monitoring. Survey data reveals that only 22.7% of anesthesia professionals in the United States have access to quantitative monitors and in Japan, using either a qualitative or quantitative monitor is not routine. Instead, anesthesia professionals rely on their subjective assessment for recovery from neuromuscular blockade based on clinical signs alone. An important factor in the inappropriate dosing of Sugammedex may be the lack of perioperative monitoring for neuromuscular blockade.

Let’s turn our attention to recurarization which refers to an increase in neuromuscular blockade after a certain time period of recovery in the absence of further administration of neuromuscular blocking medications. This is something that we have seen in the past with reversal with acetylcholinesterase inhibitors and there are now reports of this happening following Sugammadex administration. One study by Elveld and colleagues found that there was a recurrence of neuromuscular blockade after patients with a deep neuromuscular block were reversed with only a small dose of Sugammadex. Another case report revealed that an obese patient required reintubation due to recurarization in the setting of an inadequate Sugammadex dose even though the patient had a train of four ratio of 0.9 prior to the first extubation. This is definitely something we need to closely evaluate in order to help keep our patients safe when using neuromuscular blocking medications.

Why does recurarization occur? To understand this, we need to travel into the neuromuscular junction. It is here that even when muscle relaxants block 75% of the nicotinic acetylcholine receptors, we can still see normal neuromuscular transmission with normal muscle strength because of the other 25% of the receptors. In the case that we just talked about the patient had returned to normal muscle strength, but there was likely still low levels of muscle relaxants present. This is a set up for recurarization in the setting of respiratory acidosis, magnesium administration, or aminoglycoside administration. A small amount of remaining rocuronium can stay unbound in the central compartment in patients who do not receive an adequate dose of Sugammadex…and these remaining rocuronium molecules are then free to redistribute to the peripheral compartment, then onto the neuromuscular junction leading to return of impaired neuromuscular function…

…Recognition of the problem was the first step. Another important step towards improved patient safety came out in the 2019 revised JSA Guidelines for Monitoring During Anesthesia which included the following updated wording:  “Neuromuscular monitoring should be performed in patients receiving muscle relaxants and their antagonists.” The guidelines do not recommend what type of monitor to use but quantitative monitoring is preferred. Other monitors such as qualitative devices and clinical muscle function tests such as the 5-second head lift and a sustained hand grip are only able to detect train of four ratios of 0.4 or less and cannot be used to accurately determine when the patient has crossed the threshold of a train of four ratio of 0.9.

The authors report neuromuscular monitoring and availability of quantitative monitors since Japan’s national medical insurance system does not reimburse for the medical expenses of neuromuscular monitoring and the stand-alone and portable acceleromyography devices have been discontinued and are no longer for sale. The good news is that several new quantitative neuromuscular devices are no available including electromyography-based monitors, a 3-dimensional accelerometer, and monitors that include a modified blood pressure cuff with neuromuscular electrodes inside. This is especially exciting because these newer devices also have the advantages of easy calibration, simple to use and incorporation of adaptive mechanisms to compensate for postural changes while the disadvantages include newer devices that have not stood the test of time and higher cost. The authors conclude that the lack of perioperative neuromuscular monitoring has led to an increased risk of recurarization after inadequate Sugammadex dosing in Japan. Now that Sugammadex use has increased around the world, the authors acknowledge the need to warn the medical community about the risk of recurarization. Going forward, there is a need for medical device manufacturers to create neuromuscular monitors that are easy to use, safe, reliable, and affordable and there is a call to action for anesthesia professionals to use neuromuscular monitoring to guide reversal with Sugammadex so that the patient receives the appropriate dose at the right time. Stay vigilant for clinical signs of recurarization, anaphylaxis, and other postoperative complications whenever you are using muscle relaxants and reversal agents.]

And we are back to the present and ready to do a dive into some new content. Let’s talk about anaphylaxis following Sugammadex administration. For this review, we are reviewing the article, “Current Status of Sugammadex Usage and the Occurrence of Sugammadex-Induced Anaphylaxis in Japan” by Takazawa and colleagues. You can follow along by clicking on the Newsletter heading, 5th one down is Newsletter archives. Then, scroll down to the June 2018 Newsletter and the 2nd one down is our featured article today. I will include a link in the show notes as well.

The authors open with a review of Sugammadex hitting the scene and the sales history. It was first released in the European Union in 2008 followed by the release in Japan in 2010. The sales data is impressive with over $51 million dollars in Japan followed by over $11 million dollars in Spain in 2010. Over the first 8 years of Sugammadex use in Japan, it was administered to about 10% of the total Japanese population. The impressive use of Sugammadex in Japan is despite the price difference with $6 for reversal with Neostigmine and Atropine and $90 for Sugammadex. Sugammadex provides fast, reliable reversal for aminosteroid muscle relaxation and Japanese anesthesia professionals may not consider drug costs prior to administration due to the nationwide health insurance system in Japan which decreases the patients financial burden.

Given the extensive administration of Sugammadex there have been 284 cases of Sugammadex-induced anaphylaxis between April 2010 and June 2017 that were reported to the adverse events database associated with the Japanese Pharmaceuticals and Medical Devices Agency or PMDA. Let’s break down the cases.

Of the 284 cases:

157 cases were reported as anaphylactic shock

88 cases were reported as an anaphylactic reaction

4 cases were reported as anaphylactoid shock

And, 5 cases were reported as an anaphylactoid reaction.

Historically in Japan, allergic reactions with IgE were called anaphylaxis while anaphylactoid events do not involve IgE.

Data from the PMDA revealed an incidence of Sugammadex-induced anaphylaxis of about 1 in 40,000 cases. The Japanese Society of Anesthesiologists or JSA reported 95 cases of Sugammadex-induced anaphylaxis between April 2010 and October 2013 with a similar incidence of anaphylaxis related to Sugammadex administration of about 29 for every one million administration events. Keep in mind that this may underestimate the incidence of this serious adverse event due to under-reporting. Instead of a large database, if we look at a single-center study in Japan, 6 cases of anaphylaxis following Sugammadex administration were reported over the 3-year study period for an incidence of 1 in 2,500 cases or 0.039% which was considerably higher. This is similar to the incidence of anaphylaxis reported from two institutions in New Zealand that were associated with Succinylcholine and Rocuronium administration of 0.048% and 0.04% respectively.

The JSA Study of the 95 cases of anaphylaxis revealed that 76 cases had a clear onset time following Sugammadex administration. Anaphylaxis occurred within 5 minutes in 50 cases and 10 minutes in 66 cases. Other studies have reported earlier onset time for signs and symptoms within 2-4 minutes. Signs and symptoms may include bronchospasm and airway edema with decreased oxygen saturation being reported in about 50% of the reported cases of anaphylaxis. The authors caution that if there is a delayed onset time, patients may be at risk for clinical deterioration during transport to the PACU or ICU especially if they are not monitored closely.

Okay, let’s do a quick review of drugs that are reported to cause anaphylaxis in the perioperative period. The authors provide data from their own investigation into skin testing for 22 patients with perioperative anaphylaxis between May 2012 and March 2016. In 20 cases, the responsible medication was discovered. Check out Figure 2 in the article. Sugammadex tops the chart at 32% followed closely by Rocuronium at 27% and Antibiotics at 23%. Then, there is a big drop down to 9% for local anesthetics and 5% for Propofol with unknown causative agents finishing the list at 9%.

Now, for a review of the definition of anaphylaxis which must include the following:

Clinical diagnostic criteria for anaphylaxis

High blood levels of histamine and/or tryptase

And, a positive reaction to the culprit drug with skin testing.

Keep in mind that while skin testing is the gold standard for the evaluation of the causative agent following anaphylaxis, it may not be readily performed since it may induce anaphylaxis and may cause pain. Another option is in-vitro allergy testing with a blood sample and detection of IgE, but Sugammadex-specific IgE has not been reported yet. Finally, a basophil activation test may be used to help make the diagnosis of Sugammadex-induced anaphylaxis, but further evaluation is necessary.

The authors conclude with the reminder that further investigations into the incidence of Sugammadex-induced anaphylaxis are needed in Japan and worldwide since the reported events at the time of this article may have been under-reported or limited by the small size at a single institution. In order to keep patients safe following Sugammadex administration it is important to be on the lookout for anaphylaxis and continue to monitor patients closely.

Thank you for tuning in to learn even more about the vast experience of Sugammadex use for reversal of neuromuscular blockade in Japan and what we can do going forward to help keep patients safe from the risk of recurarization and anaphylaxis. Have you seen either of these events in your practice?

If you have any questions or comments from today’s show, please email us at [email protected].

Visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today.  Please keep in mind that the information in this show is provided for informational purposes only and does not constitute medical or legal advice. Have you joined the conversation on twitter? If so, we would love for you to tag us in a tweet using #APSF podcast and share your patient safety related story. Thanks for listening and we can’t wait to hear from you soon!

Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

© 2021, The Anesthesia Patient Safety Foundation